Signal Transduction by a Cytokine Receptor: Multi-Scale Computational Studies of the Membrane Associated Gp130 Receptor Complex

Abstract

Signal transduction is involved in the control of various essential biological processes such as cell growth, regeneration and apoptosis. Cytokines function as regulators of acute phase response during injury of infection, but are also involved in haematopoiesis, liver and neuronal regeneration. Two gp130 cytokine receptor forms a hexameric complex with two alpha-receptors (IL-6Rα) and two interleukin 6 (IL-6). This receptor complex formation initiates signal transduction via the JAK/ STAT pathway, i.e. tyrosine kinases of the Janus family activate signal transducers and activators of transcription. Some structural information is known about the ectodomain of the gp130 receptor complex, while the structures of the transmembrane and juxtamembrane regions are currently unknown.Here we apply multi-scale molecular dynamics simulations to shed light on some of the steps occurring within or in proximity to the membrane during signal transduction via the gp130 receptor complex. Coarse-grained (CG) simulations are performed to capture events occurring on long time-scales such as formations of protein-protein and protein-lipid interactions. The information obtained from the CG simulations is then further refined by conversion to atomistic (AT) simulations. The computational studies highlight the effect of lipid composition on protein-protein assembly within the lipid bilayer. Additionally the consequences of the juxtamembrane regions on protein-protein and protein-lipid interactions patterns have been explored and the results reveal a central role of intracellular basic residues not only on the interactions between proteins but also with the membrane. The protein-protein association has additionally been probed in physiological relevant membranes, which are complex in composition and asymmetric between the upper and lower leaflet.